PROJECT SUMMARY Epidemiological data link TBI to increased likelihood of development of AD and other neurodegenerative dementias later in life. While recent meta-analyses estimate the overall risk of dementia attributable to TBI at 5- 15%, it is still poorly understood how history of brain trauma may contribute to neurodegeneration years or even decades later. One possibility is that TBI may speed up detrimental cellular and biochemical events occurring during normal brain ageing. One of the pathways known to be affected during both, normal brain aging and more severely in neurodegenerative diseases, is autophagy. Thus, accelerated inhibition of autophagy-lysosomal function as compared to that observed in normal brain aging, could contribute to neurodegeneration observed in AD and other age-related dementias. In the course of our investigation supported by R01 NS091218 ?Function and mechanisms of autophagy-lysosomal pathway in traumatic brain injury? we demonstrated that autophagy is also inhibited after TBI. This is caused by TBI-induced lysosomal defects and is associated with profound changes in lysosomal lipid composition. Lysosomal dysfunction associated with accumulation of lipofuscin and other lipid byproducts in the endo-lysosomal compartments is also observed in aged mice. Significantly, these changes are exacerbated and accelerated by either drug or disease induced demyelinating episodes. Since TBI leads to myelin damage as well as more general perturbation of lipid metabolism in the brain, lipid-mediated damage could also lead to lysosomal inhibition after TBI and over time cause accelerated autophagy-lysosomal dysfunction as compared to that observed during normal aging, thus contributing to neurodegeneration and dementia. Based on our preliminary data, we hypothesize that TBI accelerates lysosomal accumulation of lipofuscin and other lipid byproducts as compared to normal aging, leading to lysosomal dysfunction and autophagy defects, thus predisposing to neurodegeneration. In order to test this hypothesis, we will use LC-MS/MS based lipidomic analysis and complementary IF/IHC approaches to compare changes in lysosomal lipid composition and autophagy-lysosomal function in the brains of normal aging mice and mice aging after TBI.